The present proposal outlines a series of studies designed to evaluate the perceived variability of post-operative oral-surgical pain. Two lines of basic research in pain have recently converged; first, the discovery in the brain of endogenous opiate-like compounds (endorphins); and second, the analysis of a neural substrate that underlies an endogenous analgesia-producing system. Both human and animal studies indicate that the action of the analgesia-producing system is partially mediated by endorphins. We propose to investigate in detail the hypothesis that an endorphin-mediated analgesia system (EMAS) accounts for a significant part of the variability of perceived dental post-operative pain. The experimental paradigm used in all the proposed experiments is based on manipulation and evaluatin of pain following extraction of impacted mandibular third molars. As in our previous work, pain will be assessed with a battery of subjective rating scales. Our preliminary work has shown that the relatively pure narcotic-antagonist naloxone enhances post-operative pain in opiate-naive patients. These early studies also suggested that what is referred to loosely as the analgetic placebo may be mediated by an EMAS. We propose to extend these studies to investigate dose-response, time course and other characteristics of the human EMAS. Behavioral, pharmacological, and physiologic variables will be manipulated and/or measured in a controlled environment, in order to systematically evaluate the factors which contribute to the pain experience. We propose to study factors which activate the EMAS and evaluate its possible contribution to placebo and opiate analgesia. This work will privide information that directly bears on behavioral and pharmacological management of post-operative pain.